Clopidogrel, methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-a]pyridine-5(4H)-acetate of formula (I), is a platelet-aggregation inhibitor which is effective in treating peripheral arterial diseases such as stroke, thrombosis and embolism, as well as coronary arterial diseases such as myocardial infarction and angina pectoris:

Various methods of preparing clopidogrel are described in European Patent Nos. 0,281,459, 0,466,569, 0,971,915, 0,099,802, 1,021,449, 1,404,681 and 1,353,928, and International Publication Patent No. WO 2004/094374. Among these methods, preferred in terms of commercial applicability are methods which involve resolving a racemate composed of clopidogrel of formula (I) or an intermediate thereof and its levorotatory isomer using an optical resolution agent.
For example, European Patent No. 0,281,459 discloses a method of preparing clopidogrel of formula (I) by way of reacting a racemate of clopidogrel with (1R)-(−)-10-camphorsulfonic acid to selectively form camphorsulfonate of clopidogrel, and removing the camphorsulfonate moiety therefrom (optical resolution process); and European Patent Nos. 0,099,802 and 1,353,928, by way of optically resolving an intermediate of clopidogrel racemate as described above using (1R)-(−)-10-camphorsulfonic acid, and then preparing the desired clopidogrel from the resolved intermediate (see Reaction Scheme 1).

However, these methods have the problem that the salt of clopidogrel or an intermediate thereof formed by the selective crystallization from the racemate of clopidogrel or its intermediate and (1R)-(−)-10-camphorsulfonic acid has an insufficient optical purity and must be subjected to further purification, the purification resulting in a yield reduction. In addition, it is difficult to recover (1R)-(−)-10-camphorsulfonic acid from the reaction solution for the purpose of recycling due to its high solubility in water.